Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia

Lucena-Araujo, Antonio R.; Coelho-Silva, Juan Luiz; Pereira-Martins, Diego A; Silveira, Douglas R. A.; Koury, Luisa Corrêa de Araujo; Melo, Raul Antônio Morais; Bittencourt, Rosane; Pagnano, Kátia Bórgia Barbosa; Pasqüini, Ricardo; Nunes, Éllen Almeida; Fagundes, Evandro M.; Glória, Ana; Kerbauy, Fábio R.; Chauffaille, Maria de Lourdes Lopes Ferrari; Bendit, Israel; Rocha, Vanderson; Keating, Armand; Tallman, Martin S.; Ribeiro, Raul C.; Dillon, Richard; Ganser, Arnold; Löwenberg, Bob; Valk, Peter J.M.; Sanz, Miguel Á.; Berliner, Nancy; Rego, Eduardo Magalhães

doi:10.1182/blood.2019000239

Cited by 25 publications

(17 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One particular case is FMS-like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase often mutated in AML. The most common mutations found in the internal tandem duplication (FLT3-ITD) region confers a high leukemic burden in APL and an adverse prognosis for patients treated by the ATRA/chemotherapy combination [51][52][53]. Recently, FLT3-ITD mutations were shown to severely blunt the ATRA response in animal models, precluding PML-RARA degradation and PML NB reformation [54], corroborating clinical studies.…”

Section: Mutations That Cooperate With Deregulated Rara Signaling Tomentioning

confidence: 74%

Classic and Variants APLs, as Viewed from a Therapy Response

Geoffroy

2020

Cancers

View full text Add to dashboard Cite

Most acute promyelocytic leukemia (APL) are caused by PML-RARA, a translocation-driven fusion oncoprotein discovered three decades ago. Over the years, several other types of rare X-RARA fusions have been described, while recently, oncogenic fusion proteins involving other retinoic acid receptors (RARB or RARG) have been associated to very rare cases of acute promyelocytic leukemia. PML-RARA driven pathogenesis and the molecular basis for therapy response have been the focus of many studies, which have now converged into an integrated physio-pathological model. The latter is well supported by clinical and molecular studies on patients, making APL one of the rare hematological disorder cured by targeted therapies. Here we review recent data on APL-like diseases not driven by the PML-RARA fusion and discuss these in view of current understanding of “classic” APL pathogenesis and therapy response.

show abstract

Section: Mutations That Cooperate With Deregulated Rara Signaling Tomentioning

confidence: 74%

Classic and Variants APLs, as Viewed from a Therapy Response

Geoffroy

2020

Cancers

View full text Add to dashboard Cite

show abstract

“…Routine testing of suspected genes by NGS are recommended for better prognostic prediction and individualized treatment [4]. FLT3-ITD mutational status and KMT2E gene expression levels can be used to identify those AML patients who need to be treated differently to maximize their chances of cure [31]. RNA-based FLT3-ITD measurements are recommended for risk stratification, and the relevance of AR regarding eligibility for FLT3-targeted therapy remains uncertain [12].…”

Section: Flt3mentioning

confidence: 99%

Clinical implications of recurrent gene mutations in acute myeloid leukemia

Zhang

et al. 2020

Exp Hematol Oncol

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a genetically heterogeneous clonal malignancy characterized by recurrent gene mutations. Genomic heterogeneity, patients' individual variability, and recurrent gene mutations are the major obstacles among many factors that impact treatment efficacy of the AML patients. With the application of cost-and time-effective next-generation sequencing (NGS) technologies, an enormous diversity of genetic mutations has been identified. The recurrent gene mutations and their important roles in acute myeloid leukemia (AML) pathogenesis have been studied extensively. In this review, we summarize the recent development on the gene mutation in patients with AML.

show abstract

“…However, it should be through the integration of genomics with other -omic science (i.e., epigenomics, transcriptomics and metabolomics) that we might broaden our perspective and explain the hitherto unsolved issues. This represents a great challenge for researchers in the near future, but some of the pillars seem to have already been built with the proposal, among others, of the first integrative score [141].…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the expression profile of genes such as ID1, BAALC, ERC, WT1 and KMT2E, alongside additional molecular events (such FLT3-ITD status and ∆Np73/TAp73 expression ratio), could improve the treatment outcome prediction in high-risk APL patients ( Figure 2). Consequently, an integrative score in APL (ISAPL), combining gene mutations with expression analysis, has been proposed, categorizing patients in two different sets with significant differences in remission rate, relapse and survival [141]. The ISAPL could assist in more narrowly monitoring the measurable MRD and design of improved treatment schemes.…”

Section: Gene Mutations At Diagnosis Relapse and Resistancementioning

confidence: 99%

Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene

Liquori

Ibáñez

Sargas

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Although acute promyelocytic leukemia (APL) is one of the most characterized forms of acute myeloid leukemia (AML), the molecular mechanisms involved in the development and progression of this disease are still a matter of study. APL is defined by the PML-RARA rearrangement as a consequence of the translocation t(15;17)(q24;q21). However, this abnormality alone is not able to trigger the whole leukemic phenotype and secondary cooperating events might contribute to APL pathogenesis. Additional somatic mutations are known to occur recurrently in several genes, such as FLT3, WT1, NRAS and KRAS, whereas mutations in other common AML genes are rarely detected, resulting in a different molecular profile compared to other AML subtypes. How this mutational spectrum, including point mutations in the PML-RARA fusion gene, could contribute to the 10%-15% of relapsed or resistant APL patients is still unknown. Moreover, due to the uncertain impact of additional mutations on prognosis, the identification of the APL-specific genetic lesion is still the only method recommended in the routine evaluation/screening at diagnosis and for minimal residual disease (MRD) assessment. However, the gene expression profile of genes, such as ID1, BAALC, ERG, and KMT2E, once combined with the molecular events, might improve future prognostic models, allowing us to predict clinical outcomes and to categorize APL patients in different risk subsets, as recently reported. In this review, we will focus on the molecular characterization of APL patients at diagnosis, relapse and resistance, in both children and adults. We will also describe different standardized molecular approaches to study MRD, including those recently developed. Finally, we will discuss how novel molecular findings can improve the management of this disease.

show abstract

Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia

Cited by 25 publications

References 46 publications

Classic and Variants APLs, as Viewed from a Therapy Response

Classic and Variants APLs, as Viewed from a Therapy Response

Clinical implications of recurrent gene mutations in acute myeloid leukemia

Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene

Contact Info

Product

Resources

About